Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of neurodegenerative diseases affecting a wide variety of mammals including sheep and goats (scrapie), cervid spp. (chronic wasting disease), and humans (Creutzfeldt-Jakob disease). A central event in TSE disease involves the conversion of the normal host cellular prion protein (PrPC) to a partially protease-resistant, aggregated, disease-associated isoform (PrPSc). TSE-induced pathology is usually associated with PrP-res deposition, but the mechanism of neurodegeneration is not understood. Like prion diseases, other neurodegenerative diseases involve the deposition of pathological protein aggregates including Alzheimers and Parkinsons disease. Collectively, these diseases are termed protein misfolding diseases because they are associated with the accumulation of misfolded host proteins. Critical processes for transmission of prions between and within hosts include neuroinvasion and intercellular spread of PrPSc. The membrane association of PrP via a glycosylphosphatidylinositol (GPI)-anchor may have an important role in modulating these processes. Our work in this project is focused on elucidating the role of GPI anchoring in modulating the aggregation and intercellular spread of aggregation-prone proteins. In 2010, we have: 1) completed experiments showing that GPI anchoring can allow an amyloidogenic protein to behave as a prion, work which was published in EMBO Journal;and 2) expanded upon these observations to show that transmembrane anchoring can also allow the propagation of protein aggregates as prions.